Androgen Receptor-Driven RASSF3 Upregulation Promotes CKD Progression by Inhibiting Gαs/Gq Activity to Mediate Metabolic Reprogramming [R3]

Given the well-established central role of TGF-β in CKD, we hypothesize it reprograms AR’s transcriptional network, shifting AR’s kidney function from healthy to pathogenic. Transcriptomic profiling identified RASSF3 as a critical downstream target of DHT and TGF-β1, upregulated in kidneys from male CKD patients and mice but not females.

Tubule-specific Rassf3 knockout in mice prolonged survival and protected against CKD models, whereas its overexpression exerted opposite effects. Mechanistically, RASSF3 binds Gα subunits Gq and Gαs, accelerating their GTP-to-GDP transition (active to inactive) to suppress their activity—an interaction that drives kidney tubule metabolic reprogramming and exacerbates kidney injury and CKD progression. GTPase-deficient Gq/Gαs mutants or Gq/Gαs knockout abolished RASSF3-mediated metabolic reprogramming, confirming dependence on Gq/Gαs GTPase activity.